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タイトル: | Crucial role of the Rap G protein signal in Notch activation and leukemogenicity of T-cell acute lymphoblastic leukemia. |
著者: | Doi, Keiko Imai, Takahiko Kressler, Christopher Yagita, Hideo Agata, Yasutoshi Vooijs, Marc Hamazaki, Yoko Inoue, Joe Minato, Nagahiro |
著者名の別形: | 圡井, 恵子 井上, 浄 湊, 長博 |
キーワード: | Acute lymphocytic leukaemia Leukaemia |
発行日: | 23-Jan-2015 |
出版者: | Nature Publishing Group |
誌名: | Scientific reports |
巻: | 5 |
論文番号: | 7978 |
抄録: | The Rap G protein signal regulates Notch activation in early thymic progenitor cells, and deregulated Rap activation (Rap(high)) results in the development of Notch-dependent T-cell acute lymphoblastic leukemia (T-ALL). We demonstrate that the Rap signal is required for the proliferation and leukemogenesis of established Notch-dependent T-ALL cell lines. Attenuation of the Rap signal by the expression of a dominant-negative Rap1A17 or Rap1GAP, Sipa1, in a T-ALL cell line resulted in the reduced Notch processing at site 2 due to impaired maturation of Adam10. Inhibition of the Rap1 prenylation with a geranylgeranyl transferase inhibitor abrogated its membrane-anchoring to Golgi-network and caused reduced proprotein convertase activity required for Adam10 maturation. Exogenous expression of a mature form of Adam10 overcame the Sipa1-induced inhibition of T-ALL cell proliferation. T-ALL cell lines expressed Notch ligands in a Notch-signal dependent manner, which contributed to the cell-autonomous Notch activation. Although the initial thymic blast cells barely expressed Notch ligands during the T-ALL development from Rap(high) hematopoietic progenitors in vivo, the ligands were clearly expressed in the T-ALL cells invading extrathymic vital organs. These results reveal a crucial role of the Rap signal in the Notch-dependent T-ALL development and the progression. |
著作権等: | This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/ |
URI: | http://hdl.handle.net/2433/196068 |
DOI(出版社版): | 10.1038/srep07978 |
PubMed ID: | 25613394 |
出現コレクション: | 学術雑誌掲載論文等 |
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